title: Protective effects of matrix metalloproteinase-12 following corneal injury.
abstract: Corneal scarring due to injury is a leading cause of blindness worldwide and results from dysregulated inflammation and angiogenesis during wound healing. Here we demonstrate that the extracellular matrix metalloproteinase MMP12 (macrophage metalloelastase) is an important regulator of these repair processes. Chemical injury resulted in higher expression of the fibrotic markers α-smooth muscle actin and type I collagen, and increased levels of angiogenesis in corneas of Mmp12(-/-) mice compared with corneas of wild-type mice. In vivo, we observed altered immune cell dynamics in Mmp12(-/-) corneas by confocal imaging. We determined that the altered dynamics were the result of an altered inflammatory response, with delayed neutrophil infiltration during the first day and excessive macrophage infiltration 6 days later, mediated by altered expression levels of chemokines CXCL1 and CCL2, respectively. Corneal repair returned to normal upon inhibition of these chemokines. Taken together, these data show that MMP12 has a protective effect on corneal fibrosis during wound repair through regulation of immune cell infiltration and angiogenesis.
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco, CA, USA. matilda.chan@ucsf.edu
authors.forename: Matilda F
authors.initials: MF
authors.lastname: Chan
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Anthony
authors.initials: A
authors.lastname: Bertrand
authors.forename: Amy-Jo
authors.initials: AJ
authors.lastname: Casbon
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Lin
authors.forename: Inna
authors.initials: I
authors.lastname: Maltseva
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D024042:Collagen Type I / Q000096:biosynthesis; D003315:Cornea / Q000276:immunology / Q000378:metabolism; D065306:Corneal Injuries; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000517:prevention & control*; D007249:Inflammation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics; D020556:Neutrophil Infiltration / Q000276:immunology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D000199:Actins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D024042:Collagen Type I; C475895:Cxcl1 protein, mouse; C544013:alpha-smooth muscle actin, mouse; D053508:Matrix Metalloproteinase 12
keywords: Corneal inflammation; Matrix metalloproteinases; Wound repair